Antigen-specific T lymphocyte activation occurs through the clonally distributed T cell receptor. The available set of alpha beta T cell receptors is dictated by both positive and negative intrathymic selection events. The molecular basis of this selection, in particular, how bias for self-MHC presented peptides is achieved without corresponding deletions of these clones during establishment of self-tolerance, is unknown. Furthermore, the quantitative and qualitative relationships between receptor occupancy and signaling for differentiation, whether in the thymus or of mature T cells in the periphery, is also poorly understood. This project uses cellular and molecular tools to study the development of the T cell repertoire and the activation of T cells upon ligand engagement of alpha beta and non-clonal surface receptors. IL-2 (T cell growth factor) production by CD4 T cells is known to be very dependent on co-stimulatory signals distinct from those arising from occupancy of the clonally distributed alpha beta T cell receptor. Investigation of a prototypic Th1-type T cell clone specific for cytochrome c and EalphaEbetak unexpectedly revealed that addition of the known peptide ligand recognized by this cell interfered with alloantigen stimulation of IL-2 production by the clone. Inhibition by added peptide was not due to competition for creation of the alloantigen itself, to over-stimulation of the clone, or to interference with the generation of second messengers inside the T cell sufficient for other effector responses such as IL-3 production. Instead, peptide complexes involving the mutant class II molecule appeared to interact with the T cell receptor, interfering with either the production of or intracellular action of the critical co-stimulatory signals needed for IL-2 gene activation. These observations provide a new view of the relationship between T cell receptor occupancy and the response to such occupancy in the context of the T cell-antigen presenting cell interaction. This may provide an important clue to the control of thymic selection, as well as the initiation and deviation of immune responses. These findings may provide a new approach to the control of autoimmune diseases characterized by oligoclonal T cell responses and a means of controlling the type of effector responses elicited by component vaccine formulations.